Recent advances in breast cancer biology have demonstrated that the loss of tumor suppressors, such as p53, and over-expression of oncogenes, including Mouse Double Minute 2 (MDM2), contribute to the poor response to treatment and poor prognosis in breast cancer patients. The MDM2 oncogene is amplified and over-expressed in a number of human malignancies, including breast cancer. High levels of the MDM2 protein often correlate with decreased survival rates in patients. The MDM2 oncogene is a negative regulator of the tumor suppressor p53, which regulates the cell cycle, maintains the genomic integrity of cells, and controls the cellular response to DNA damage. It also directly binds to p53, represses the transcriptional activity of p53, and promotes p53 degradation. The MDM2 oncoprotein also has p53-independent activities. In addition to inhibiting apoptosis by affecting both pro-apoptotic and anti-apoptotic proteins, MDM2 also alters cell cycle regulation, DNA replication, and DNA repair.
MDM2 oncogene activation has been suggested to be associated with cancer progression and metastasis. Breast cancer is an example where the association has been found. To date, most MDM2 inhibitors have been designed to block the MDM2-p53-binding interphase and have low or no efficacy against advanced cancer with mutant or deficient p53. Furthermore, many treatments cause host toxicity.
Accordingly, there is a need for new anticancer therapies that utilize compounds to bind with MDM2 and inhibit MDM2 expression while minimizing toxicity and promoting anticancer activity independent of p53 status.